Preparation of metal mesoporphyrin compounds

a technology of mesoporphyrin and halide compounds, which is applied in the direction of organic chemistry, iron group organic compounds without c-metal linkages, iron organic compounds, etc., can solve the problems of difficult to drive the reaction to completion, degradation of intermediate products, and process unsuitable for industrial scale up, so as to reduce degradation and increase degradation. , the effect of short reaction tim

Inactive Publication Date: 2008-05-20
MALLINCKRODT HOSPITAL PRODUCTS IP LTD
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0012]Alternatively and preferably, the reactor may be pressurized with hydrogen gas prior to the heating step. Pressurizing the reactor with hydrogen prior to heating, in the first step of the process, reduces degradation, while exceeding the times and the temperatures set out above for the first step increases degradation. On the other hand, shorter reaction times and lower temperatures will lead to undesirable decreases in conversion, leading to low product yields. The second step as defined above completes the conversion of the hemin (Protoporphyrin IX iron (III) chloride) to mesoporphyrin IX formate.

Problems solved by technology

This process is reported to reduce the amount of the unidentified impurity; however, the reaction is difficult to drive to completion without decomposition of the intermediate product.
Additionally, those methods in which hydrogenation is carried out at lower temperatures yield incomplete reactions, and when higher temperatures are used, degradation of the intermediate product is observed.
Furthermore, the above referenced procedures require exceedingly high solvent volumes, thus making the process unsuitable for industrial scale up, since isolation of mesoporphyrin IX dihydrochloride or its free base is performed using a filtration process.
Such filtrations and subsequent washings of the products are time-consuming, making the large-scale isolations costly and difficult.
Additionally, the limited stability of mesoporphyrin IX in hydrochloric acid at the elevated temperatures required to form the dihydrochloride also complicates the industrial scale up of this process.

Method used

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  • Preparation of metal mesoporphyrin compounds
  • Preparation of metal mesoporphyrin compounds
  • Preparation of metal mesoporphyrin compounds

Examples

Experimental program
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Effect test

example 1

[0033]Preparation of Mesoporphyrin IX Formate

[0034]A 2000 ml hydrogenation vessel was charged with 40.0 g hemin, 4.0 g 5% Pd / C (50% water by weight), and 800 ml 96% formic acid. Since hemin and mesoporphyrin IX formate as well as all reaction intermediates are reportedly light sensitive materials, care was taken throughout this entire procedure to minimize the exposure of the reaction to visible or ultraviolet light.

[0035]The vessel was flushed with a nitrogen flow for 10 minutes. With vigorous stirring, it was then pressurized to 50 psi with hydrogen for ten minutes; then depressurized, and the cycle repeated. The vessel was further pressurized to 50 psi with hydrogen and the temperature was raised to 90° C. over approximately 20 minutes.

[0036]The hydrogenation reaction was maintained at 90° C. and 45-55 psi for 1-1.5 hours. The reaction mixture was not stable for extended periods of time at 90° C. The time at this temperature was sufficient to dissolve all hemin and convert the ma...

example 2

[0038]Preparation of Substantially Pure Tin Mesoporphyrin Chloride (Tin (IV) Mesoporphyrin IX Dichloride or Stannsoporfin).

[0039]A dark 1000 ml three-necked, round-bottom flask equipped with a mechanical stirrer, condenser, bubbler, and an aeration tube was charged with 30.0 g mesoporphyrin IX formate, 34.5 g tin (II) chloride, 7.1 g ammonium acetate, and 600 ml acetic acid. The suspension was stirred at 20-25° C. for 30 minutes. Mesoporphyrin IX formate and tin mesoporphyrin as well as all reaction intermediates are reportedly light sensitive materials therefore care was taken throughout this entire procedure to minimize the exposure of the reaction to light.

[0040]The reaction was warmed to reflux, with aeration, for 3 to 4 hours. The reaction was shown to be stable at 110-115° C. for up to 48 hours. Once complete, the reaction mixture was cooled to 60-70° C. and 300 ml water was added while cooling to 20-25° C. over 60 minutes. The suspension was filtered under reduced pressure. T...

example 3

[0041]Further Purification of Crude, Substantially Pure Tin (IV) Mesoporphyrin Chloride (Tin (IV) Mesoporphyrin IX Dichloride or Stannsoporfin).

[0042]A darkened, 250 ml, one-neck, round-bottom flask equipped with a magnetic stirbar and nitrogen purge was charged with: 10.0 g tin (IV) mesoporphyrin chloride (tin (IV) mesoporphyrin IX dichloride), 125 ml water, and 4 ml 28% ammonium hydroxide, a sufficient amount of ammonium hydroxide to adjust the pH to 9.0-10.0. The suspension was stirred at 20-25° C. for 20-30 minutes to effect dissolution. As tin (IV) mesoporphyrin is light sensitive, dark conditions were maintained throughout this reaction sequence.

[0043]The flask was charged with 0.5 g Darco KB, and a 1.5 g Celite. The dark suspension was stirred at 20-25° C. for 1 hour. The suspension was filtered under reduced pressure through a bed of celite using a 5.5 cm Buchner funnel. The flask and filtercake were rinsed with 2×10 ml water. A dark, 1L, one-neck, round-bottom flask equippe...

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Abstract

A method of preparing metal mesoporphyrin compounds is described. A metal mesoporphyrin compound may be formed by forming a novel mesoporphyrin IX intermediate compound and then converting the mesoporphyrin IX intermediate to a metal mesoporphyrin compound through metal insertion. The novel intermediate compound may be formed by a catalytic hydrogenation of hemin in acid and subsequent recovery.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS[0001]The present application is a continuation-in-part of U.S. application Ser. No. 10 / 453,815, filed on Jun. 3, 2003 now U.S. Pat. No. 7,818,763, which claims the benefit of U.S. Provisional Application No. 60 / 385,498, filed on Jun. 4, 2002, the disclosures of which are incorporated by reference herein.BACKGROUND OF THE INVENTION[0002]The present invention generally relates to metal mesoporphyrin halide compounds and processes for their preparation. More specifically, it relates to processes for making novel intermediate compounds, which can be converted to such mesoporphyrin halide compounds.[0003]Tin (IV) mesoporphyrin IX dichloride or stannsoporfin is a chemical compound having the structure indicated in FIG. 1. It has been proposed for use, for example, as medicament in the treatment of various diseases including, for example, psoriasis (U.S. Pat. No. 4,782,049 to Kappas et al.) and infant jaundice (for example, in U.S. Pat. Nos. 4,684,63...

Claims

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Application Information

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Patent Type & Authority Patents(United States)
IPC IPC(8): C07D487/22C07F7/00C07F15/02
CPCC07D487/22C07F7/003C07F15/025
Inventor VUKOVICH, ROBERTLEVINSON, BENJAMINDRUMMOND, GEORGE S.CAROSELLI, ROBERTANTCZAK, KAZIMIERZ G.BOUCHER, CHRISTOPHERMORTIMER, RICHARDLEVIN, DANNYCOOKE, KEITH A.
Owner MALLINCKRODT HOSPITAL PRODUCTS IP LTD
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